US5347029AExpiredUtility

Dialkyl (dialkoxyphosphinyl)methyl phosphates as anti-inflammatory agents

79
Assignee: UPJOHN COPriority: Jun 19, 1991Filed: Dec 16, 1993Granted: Sep 13, 1994
Est. expiryJun 19, 2011(expired)· nominal 20-yr term from priority
Inventors:Roy A. Johnson
C07F 9/6506C07F 9/657181C07F 9/5728C07F 9/4006C07F 9/58A61P 29/00
79
PatentIndex Score
20
Cited by
14
References
15
Claims

Abstract

Provided are novel dialkyl (dialkoxyphosphinyl)methyl phosphates of formula ##STR1## which am useful as anti-inflammatory and anti-arthritic agents. The compounds are synthesized from the reaction of tetraethyl oxiranylidenebisphosphonate and unsubstituted or alkyl-amines. Representative compounds include 2-(benzylamino)-1-(diethoxyphosphinyl)ethyl phosphonic acid diethyl ester, 1-(diethoxyphosphinyl)-2-[2'-(1', 2', 3', 4'-tetrahydro)napthylamino]ethyl phosphonic acid diethyl ester, 2-(3-fluorobenzylamino)-1-(diethoxyphosphinyl)ethyl phosphonic acid diethyl ester, and 5,5 -dimethyl-2-[2-(3-fluorobenzyl)amino-1-[(5,5-dimethyl-1,3,2-dioxaphosphorinan-2-yl)oxy]ethyl]-1,3,2-dioxaphosphorinane P,2-dioxide.

Claims

exact text as granted — not AI-modified
I claim: 
     
       1. A compound of formula wherein   R 1  is independent and selected from the group consisting of hydrogen, C 1  -C 10  alkyl, --C 6  H 5  ;   adjacent R 1  taken together may be --CH 2  (CH 2 ) n  CH 2  --or --CH 2  C(CH 3 ) 2  CH 2  --;   R 2  is selected from the group consisting of hydrogen, C 1  -C 10  alkyl, C 3  -C 7  cycloalkyl, --CH 2  CH═CH 2 , --CH 2  CH 2  OH, --CH 2  (CH 2 ) n  Ar, --CH 2  CH 2  OCH 2  Ar, --CH(C 6  H 5 ) 2 , and 1 '- or 2 '-(1',2',3',4'-tetrahydro)naphthylene;   R 3  is selected from the group consisting of hydrogen, C 1  -C 10  alkyl, --CO(CH 2 ) m  CH 3 , --CO 2  CH 2  Ar, and --COAr;   n is 0, 1, or 2;   m is 0 thru 9;   Ar is selected from the group consisting of (a) phenyl, 1- or 2-naphthyl, 3-indolyl, 2-, 3-, or 4-pyridinyl, or 1-imidazolyl,   (b) phenyl optionally substituted with 1 thru 5 --F or --Cl,   (c) phenyl optionally substituted with 1 thru 3 --Br, --I, --CF 3 , --R 4 , or --OR 4 ,   (d) phenyl substituted with --COOR 4 , --OCOR 4 , --SO 2  NH 2 , --NHSO 2  R 4 , and --NHCOR 4  ;     R 4  is C 1  -C 5  alkyl; provided, however, when R 1  is --C 2  H 5 , neither R 2  nor R 3  may be --C 3  H 7  ;     and pharmaceutically acceptable salts thereof.   
     
     
       2. A compound according to claim 1 wherein R 1  is independent and selected from the group consisting of C 1  -C 10  alkyl;   R 2  is selected from the group consisting of C 1  -C 10  alkyl, C 3  -C 7  cycloalkyl, --CH 2  CH═CH 2 , --CH 2  CH 2  OH, --CH 2  (CH 2 ) n  Ar, --CH 2  CH 2  OCH 2  Ar, --CH(C 6  H 5 ) 2  and 1'- or 2'-(1',2',3',4'-tetrahydro)naphthylene; and   R 3  is selected from the group consisting of hydrogen, C 1  -C 10  alkyl, --CO 2  CH 2  Ar, and --COAr.   
     
     
       3. A compound according to claim 2 wherein R 2  is selecled from the group consisting of C 1  -C 10  alkyl, C 3  -C 7  cycloalkyl, --CH 2  CH═CH 2 , --CH 2  CH 2  OH, --CH(C 6  H 5 ) 2 , and 1'- or 2'-(1', 2', 3', 4'-tetrahydro)naphthylene; and   R 3  is hydrogen.   
     
     
       4. A compound according to claim 3 selected from the group consisting of 2-(cyclohexylamino)-1-(diethoxyphosphinyl)ethyl phosphoric acid diethyl ester,   1-(diethoxyphosphinyl)-2-[(2'-hydroxy)ethylamino]ethyl phosphoric acid diethyl ester,   1-(diethoxyphosphinyl)-2-[2'-(1',2',3',4'-tetrahydro)naphthylamino]ethyl phosphoric acid diethyl ester,   1-(diethoxyphosphinyl)-2-(2'-propen-1'-ylamino)ethyl phosphoric acid diethyl ester, and   1-(diethoxyphosphinyl)-2-(diphenylmethylamino)ethyl phosphoric acid diethyl ester.   
     
     
       5. A compound according to claim 2 wherein R 2  is --CH 2  (CH 2 ) n  Ar;   R 3  is hydrogen;   Ar is selected from the group consisting of (a) phenyl,   (b) phenyl substituted with 1 thru 5 --F or --Cl,   (c) phenyl substituted with 1 thru 3 --Br, --I, --CF 3 , --R 4 , or --OR 4 ,   (d) phenyl substituted with --COOR 4 , --OCOR 4 , --SO 2  NH 2 , --NHSO 2  R 4 , and --NHCOR 4  ; and     R 4  is C 1  -C 5  alkyl.   
     
     
       6. A compound according to claim 5 selected from the group consisting of 2-(benzylamino)-1-(diethoxyphosphinyl)ethyl phosphoric acid diethyl ester,   2-[(3'-fluoro)benzylamino]-1-(diethoxyphosphinyl)ethyl phosphoric acid diethyl ester, and   (1RS,1'R)-1-(diethoxyphosphinyl)-2-[(1'-phenyl)ethylamino]ethyl diethyl ester.   
     
     
       7. A compound according to claim 6 which is 2-(benzylamino)-1-(dicthoxyphosphinyl)ethyl phosphoric acid diethyl ester. 
     
     
       8. A compound according to claim 6 which is 2-[(3'-fluoro)benzylamino]1-(diethoxyphosphinyl)ethyl phosphoric acid diethyl ester. 
     
     
       9. A compound according to claim 2 wherein R 2  is --CH 2  (CH 2 ) n  Ar;   R 3  is hydrogen; and   Ar is selected from the group consisting of 1- or 2-naphthyl, 3-indolyl, 2-, 3-, or 4-pyridinyl, or 1-imidazolyl.   
     
     
       10. A compound according to claim 9 selected from the group consisting of 1-(diethoxyphosphinyl)-2-[(3'-pyridyl)methylamino]ethyl phosphoric acid diethyl ester,   1-(diethoxyphosphinyl)-2-[2'-(3'-indolyl)ethylamino]ethyl phosphoric acid diethyl ester, and   1-(diethoxyphosphinyl)-2-[3'-(1'-imidazolyl)propylamino]ethyl phosphoric acid diethyl ester.   
     
     
       11. A compound according to claim 10 which is 1-(diethoxyphosphinyl)-2-[(3'-pyridyl)methylamino]ethyl phosphoric acid diethyl ester. 
     
     
       12. A compound according to claim 2 wherein R 2  is selected from the group consisting of --CH 2  CH═CH 2 , --CH 2  (CH 2 ) n  Ar, and --CH 2  CH 2  OCH 2  Ar;   R 3  is selected from the group consisting of --CO 2  CH 2  Ar, --CO(CH 2 ) m  CH 3 , and --COAr;   Ar is selected from the group consisting of (a) phenyl,   (b) phenyl optionally substituted with 1 thru 5 --F or --Cl, and   (c) phenyl optionally substituted with 1 thru 3 --Br, --I, --CF 3 , --R 4 , or --OR 4 ,     R 4  is C 1  -C 5  alkyl.   
     
     
       13. A compound according to claim 12 selected from the group consisting of 2-[acetyl(3'-fluoro)benzylamino]-1-(diethoxyphosphinyl)ethyl phosphoric acid diethyl ester, and   2-[benxyloxyformyl(2'-propen-1'-yl)amino]-1-(diethoxyphosphiny)ethyl phosphoric acid diethyl ester.   
     
     
       14. A compound according to claim 1 wherein adjacent R 1  taken together are --CH 2  (CH 2 ) n  CH 2  --or --CH 2  C(CH 3 ) 2  CH 2  --.   
     
     
       15. A compound according to claim 14 selected from the group consisting of 5,5-dimethyl-2-[2-(3-fluorobenzyl)amino-1-[(5,5-dimethyl-1,3,2-dioxaphoshorinan-2-yl) oxy]ethyl]-1,3,2-dioxaphosphorinane P,2-dioxide, and   5,5-dimethyl-2-[2-(2-phenyl)ethylamine-1-[(5,5-dimethyl-1,3,2-dioxaphosphorinan-2-yl) oxy]ethyl]-1,3,2-dioxaphosphorinane P,2-dioxide.

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